HAI Book 2025 - Flipbook - Page 440
McKay, Nicole
113
White matter microstructural degeneration is spatially correlated
with tau accumulation in Autosomal Dominant Alzheimer disease
Nicole McKay1, Stephanie Doering1, David Hoagey1, Jeremy Strain1, Peter Millar1, Jason
Hassenstab1, Chengjie Xiong1, Eric McDade1, Randall Bateman1, Brian Gordon1, Tammie
Benzinger1
1
Washington University School of Medicine, St. Louis, MO, US
Neurodegeneration in Alzheimer disease (AD) has traditionally been associated with grey matter, despite evidence
that concurrent white matter (WM) deterioration occurs. Amyloid deposition correlates with WM hyperintensities,
whereas tau uniquely impacts WM microstructure, potentially due to axonal injury from its prion-like spread along
WM pathways. Tau accumulation and WM degeneration begin prior to clinical symptom onset, emphasizing their
pivotal role in AD manifestation. However, the link between tau accumulation and WM degeneration is still
underexplored. Autosomal dominant AD (ADAD) has a known genetic trigger and relatively uniform phenotypic
expression that can be leveraged to investigate preclinical pathophysiology. Those with ADAD exhibit early
symptoms with fewer age-related comorbidities, and the high penetrance of these mutations enables precise
disease staging relative to expected year of symptom onset. Using data from the Dominantly Inherited Alzheimer
Network, we characterized WM integrity in ADAD mutation carriers and non-carrier siblings using fractional
anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. First, we utilized tract-based spatial statistics
to summarize these metrics across the whole brain relative to disease severity. Probabilistic tractography was
also conducted, and summary WM indices were extracted from projections of the cingulum bundle, tracts
connected to regions of highest tau accumulation in ADAD. Our results indicate that at the global level,
abnormality in WM microstructure occurs relatively late in AD. However, in tracts seeded from the precuneus,
microstructural changes begin to emerge approximately five years prior to symptom onset. This emergence of
abnormality is earlier than changes observed in other pathways, supporting hypotheses that WM microstructural
degeneration may be spatially correlated with tau. Given that WM is critically important for transduction and
integration of signals across disparate brain regions, the continued characterization of tau and WM pathology
progression may provide important insight into the mechanism through which tau drives cognitive symptom
onset.
Keywords: autosomal dominant, tau, white matter,
HAI2025 - 440
